BCL-3 expression is an important determinant of the DNA damage response in colorectal cancer


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Adam Chambers1,Chris Parker2,Eleanor Mortensson2,Alice Sherrard2,Kat Gash2,Ann Williams2
1,2University of Bristol

Abstract

Background

DNA damaging therapy (radiation/platinum-based agents) is a mainstay of treatment in locally advanced rectal cancer; although, a significant number of patients will have a poor response: understanding why is critical for improving patient care. BCL-3 is an important pro-survival gene in colorectal tumour cells and as BCL-3 is overexpressed in a subset of rectal cancers, we hypothesised that BCL-3 expression confers resistance to DNA damaging agents. The aim was to investigate the effect of BCL-3 expression on the response of colorectal cancer cells to DNA damage.

Method

Immunohistochemistry for BCL-3 was performed on patient tissue, obtained before and after neo-adjuvant chemo-radiation (ASPIRE cohort study) for rectal cancer. Rectal (SW1463) and colon (LS174T and HCA7/P) cancer cells were exposed to DNA damage either by γ-irradiation (Caesium137 source, 1 or 2.5 Gy) or oxaliplatin (10 μM). BCL-3 was suppressed using siRNA. Cell viability was measured using the ratio of floating cells to adherent cells and/or using a crystal violet assay. Immunofluorescence was used to determine γH2AX foci formation following irradiation.

Results

BCL-3 suppression results in the increased sensitivity to DNA damage induced by γ-irradiation or oxaliplatin; demonstrated by a reduction in cell yield and an increase in the number and persistence of γH2AX foci following γ-irradiation. Preliminary data from the ASPIRE cohort study suggested BCL-3 expression may predict response to neo-adjuvant therapy in rectal cancer, with high BCL-3 expression resulting in a poorer tumour regression grade (TRG).

Conclusion

These data suggest that BCL-3 expression plays an important role in the response of rectal cancer cells to neo-adjuvant chemo-radiotherapy in-vivo and in-vitro. Furthermore, BCL-3 could play a novel role in the DNA damage response (DDR). Work is currently underway to understand the mechanism by which BCL-3 alters the DDR. Targeting BCL-3 in those patients with high expression may be an attractive addition to current therapy.